Jung-min Lee, Alexandre Buckley de Meritens, Dominic H. Moon, and Elise C. Kohn
BACKGROUND AND EPIDEMIOLOGY
■Ovarian cancer is the second most common gynecologic malignancy, the most common cause of gynecologic cancer death, and fifth leading cause of cancer death in women in the United States.
■In 2012, approximately 22,280 cases will be diagnosed, resulting in 15,500 deaths.
■The median age at diagnosis is 63, with ~70% of new diagnoses at or beyond 55 years of age.
■Lifetime risk of developing epithelial ovarian cancer (EOC) is approximately 1 in 70 (1.4%). It can be as high as 60% and 30% for patients with deleterious BRCA1 and BRCA2 mutation (BRCA1/2mut), respectively.
■The majority of EOCs (~75%) are diagnosed at advanced stage (III/IV; Fig. 17.1).
■The EOC overall 5-year survival is 44%, with >70% of early-stage (I/II) patients alive at 5 years.
PATHOLOGY
■Epithelial histology accounts for 90% of all ovarian cancers. Serous, mucinous, endometrioid, clear cell, and transitional cell carcinomas are EOC.
•EOCs are moving into a two-type classification system:
•Type I tumors include low-grade serous and endometrioid, mucinous, clear cell, and transitional cell carcinomas.
οType I tumors generally exhibit low-grade histopathologic features (with the exception of clear cell and endometrioid carcinomas) and appear to arise from well-defined ovarian precursor lesions. Low-grade serous and mucinous carcinomas can progress from their respective serous or mucinous cystadenomas and borderline or low malignant potential (LMP) counterparts.
οType I tumors may also develop from ectopic endometriosis to the ovary or peritoneal surface yielding clear cell and low-grade endometrioid carcinomas.
οLMP neoplasms account for approximately 15% of EOC. They are defined by limited layers of stratified epithelial proliferation, without ovarian stromal invasion.
οApproximately 67% of low-grade serous cancers carry oncogenic mutations in BRAF and KRAS; these neoplasms may have an indolent course.
οNearly 80% of mucinous ovarian cancers have KRAS mutations. If there is extension beyond the ovary, the appendix must be cleared of malignancy for a pathologic conclusion of mucinous carcinoma of the ovary.
•Type II tumors include high-grade serous carcinoma, high-grade endometrioid carcinomas, and undifferentiated carcinoma.
οType II tumor precursor lesions are hypothesized to be clonal expansions of transformed epithelial cells of the fallopian tube fimbria that spread to the ovaries.
οNearly all type II tumors are associated with abnormalities in TP53, with dysregulating mutations being most common.
οType II cancers are more aggressive and commonly disseminated within the abdominal cavity upon presentation.
οHigh-grade serous ovarian, fallopian tube, and primary peritoneal carcinomas are now treated as a single clinical entity (“EOC”).
■The remaining 10% of ovarian cancers consist of sex-cord stromal or germ cell histology.
•Sex-cord stromal tumors are mesenchymal and include granulosa cell and Sertoli-Leydig cell tumors. Granulosa cell tumors account for 70% of sex-cord stromal tumors and may produce estrogen. Sertoli-Leydig cell tumors may produce testosterone.
•Germ cell neoplasms include dysgerminoma, teratoma, and yolk sac (endodermal sinus) tumors. Malignant germ cell tumors are treated similarly to testicular cancer.
FIGURE 17.1 A flow chart for ovarian cancer FIGO staging. Patients are staged at diagnosis based on the extent of spread of the ovarian cancer. Correct staging is critical as it impacts treatment decisions.
RISK FACTORS
■Table 17.1 lists risk factors for ovarian cancer.
PREVENTION
■The use of oral contraceptives is protective against EOC for the general population. Increasing duration of use is associated with larger reductions in EOC risk.
■Risk reduction salpingo-oopherectomy (RRSO) has been shown to reduce the lifetime risk of ovarian/tubal/peritoneal cancer in high-risk women to less than 5%. RRSO is recommended for high-risk women, those with familial ovarian cancer syndromes and/or BRCA1/2mut. Surgery is recommended after completion of childbearing and, where feasible, approximately 10 years earlier than the age of diagnosis of the youngest affected family member.
■RRSO has been shown to decrease the risk of breast cancer up to 50% in BRCA1/2mut patients.
■RRSO is not recommended for women at average risk.
SCREENING
■The 2012 Reaffirmation Recommendation Statement of the U.S. Preventive Services Task Force reiterated its recommendation against screening for EOC in women who are asymptomatic and without known genetic mutations that increase its risk.
•Mounting evidence suggests that annual screening with transvaginal ultrasonography (TVU) and serum cancer antigen 125 (CA-125) does not reduce mortality. High false-positive rates leading to intervention are associated with subsequent harm, such as unnecessary surgical intervention.
•Women with a family history of breast/ovarian cancer should be offered genetic counseling. Refer to the NCI website for details: http://www.cancer.gov/cancertopics/factsheet/Risk/BRCA
■Familial ovarian cancer syndrome patients and known BRCA1/2mut carriers who have not undergone RRSO may be offered screening consisting of a pelvic examination, TVU, and a CA-125 blood test every 6 months beginning between the ages of 30 to 35 years, or 5 to 10 years earlier than the earliest age of first EOC diagnosis in the family. There are no data demonstrating survival benefit of screening high-risk patients.
■Women with high-risk families in whom deleterious mutations are not found (BRCA1/2, Lynch syndrome–associated genes) are treated similarly to those in whom genetic risk is identified. RRSO is recommended; absent RRSO, screening as for high-risk women is reasonable.
SERUM BIOMARKERS
■CA-125 is a high-molecular-weight glycoprotein and marker of epithelial tissue turnover produced by ovarian, endocervical, endometrial, peritoneal, pleural, colonic, and breast epithelia.
•CA-125 is increased in ~50% of early-stage and >90% of advanced stage EOC. It is elevated most commonly in serous histology.
•Specificity of CA-125 for ovarian cancer is poor. It can be increased in many benign conditions, such as endometriosis, first trimester pregnancy, pelvic inflammatory disease, uterine fibroids, benign breast disease, cirrhosis, and in response to pleural or peritoneal effusions of any cause, and other epithelial malignancies.
•CA-125 is FDA approved for use as a biomarker for monitoring EOC response to treatment and recurrence. It is neither approved nor recommended for screening.
•The reliability of following CA-125 concentrations during molecularly targeted therapy is unknown.
■Human epididymis protein 4 (HE4) is a glycoprotein also expressed in some EOC. It is increased in >50% of tumors that do not also express CA-125.
•HE4 testing is FDA approved as a biomarker for monitoring EOC recurrence and response to treatment. It is neither approved nor recommended for screening.
DIAGNOSIS AND EVALUATION
■EOC is not a silent disease. Symptoms are present, though nonspecific.
■Several studies suggest usefulness of a symptom index tool to identify women who may have EOC: new (within 1 year) and persistent (more than 12 times/month) pelvic/abdominal pain, increased abdominal size/bloating, difficulty eating/feeling full, and urinary urgency/frequency should trigger evaluation by a gynecologic oncologist.
■Stromal tumors can produce virilization, precocious puberty, amenorrhea, and/or postmenopausal bleeding, depending on patient age, and type and amount of ectopic hormone produced.
■The preoperative workup of a patient with a suspected ovarian malignancy is summarized in Table 17.2.
■Early referral to a gynecologic oncologist is recommended. The extent and quality of surgical debulking have important prognostic value and are an integral part of the upfront management of an EOC patient.
TREATMENT
Surgery
■Proper EOC diagnosis and staging require laparotomy with en bloc TAH/BSO tumor removal, abdominal fluid sampling, tumor debulking, and pathologic assessment of the abdomen, including diaphragms, paracolic gutters, and serosal surfaces. Unilateral salpingo-oophorectomy can be considered in women with stage I grade 1/2 tumors who wish to preserve fertility. Completion of salpingo-oopherectomy is recommended upon completion of child-bearing.
■The primary goal of EOC surgery is complete debulking. Data indicate better outcome for women undergoing surgical debulking by a gynecologic oncologist.
■Optimal debulking, defined as <1 cm maximal diameter residual disease, has positive prognostic value; no visible residual disease yields an even better prognosis.
■Stage I disease with favorable prognostic features (grade 1/2, stage IA/B, non–clear cell histology) can be treated by surgery alone.
■Complete primary debulking surgery (PDS) is still considered the gold standard in the United States. Neoadjuvant chemotherapy (NACT) followed by surgery or with interval debulking surgery yields similar overall survival (OS) to PDS.
■Second-look laparoscopy/laparotomy is no longer supported in the United States.
Initial Chemotherapy
■Stage IC disease with favorable prognostic features can be treated by surgery followed by limited course platinum-based chemotherapy (three cycles; GOG-157); six cycles are recommended for poor prognosis feature stage IC.
■The recommended standard of care adjuvant therapy for optimally debulked advanced stage III patients is a combination of IV paclitaxel and intraperitoneal (IP) cisplatin/paclitaxel chemotherapy. It is unclear if the benefit was due to the dose density, site of administration, or both factors.
■The standard of care NACT or adjuvant therapy for patients with suboptimally debulked stage III/any stage IV disease and patients who cannot tolerate IP chemotherapy is six cycles of IV carboplatin and IV paclitaxel every 21 days.
■NACT and adjuvant chemotherapy regimens are summarized in Table 17.3.
■The GOG 262 phase 3 trial evaluating the efficacy of dose dense weekly paclitaxel with carboplatin AUC 6 is maturing.
■Carboplatin and cisplatin are equally effective in the treatment of EOC; carboplatin has reduced renal, auditory, and neurotoxicity compared to cisplatin but greater and cumulative marrow effects (GOG-158).
■Paclitaxel and docetaxel have been shown to yield similar outcomes in adjuvant therapy (SCOTROC1).
■Carboplatin dosing should be based on the Calvert formula for calculating AUC (http://ctep.cancer.gov/content/docs/Carboplatin_Information_Letter.pdf) dosing of carboplatin [AUC × (GFR + 25)], where GFR is the calculated glomerular filtration rate. If a patient’s GFR is estimated based on serum creatinine measurements by the IDMS method, FDA recommends that physicians consider capping the dose of carboplatin for desired exposure (AUC) to avoid potential toxicity due to overdosing.
■Patients can demonstrate hypersensitivity to paclitaxel with the initial treatment doses due to an anaphylactoid reaction to either the paclitaxel and/or its vehicle. Treatment can be changed to docetaxel, which has a different vehicle.
■Platinum hypersensitivity is an anaphylactic, true allergic reaction and presents in later cycles (usually >6 to 10 exposures).
•Cisplatin and carboplatin can be cross-substituted, depending on the severity of the reaction. The two agents can have cross-sensitivity because the bioactive moiety is the same.
•Women having a history of platinum allergy may be retreated using slow infusion and premedication with steroids and H1/H2 blockers.
■Phase 3 studies suggest that bevacizumab given during adjuvant carboplatin/paclitaxel and in maintenance prolongs PFS but may not improve OS (GOG218 and ICON7).
■A meta-analysis of six randomized maintenance trials confirmed no improvement in OS (HR 1.07; 95% CI 0.91 to 1.27; N = 902). This analysis did not include bevacizumab maintenance therapy.
Recurrent or Persistent Disease
■Recurrence occurs in >80% of stage III/IV patients; recurrent EOC is not curable, although subsequent complete remissions may occur.
■No OS benefit was observed in a RCT comparing early treatment of relapse (increased CA-125 alone) versus observation until symptoms or physical examination trigger disease assessment (MRC OV05/EORTC 55955).
■Secondary cytoreduction surgery is recommended for women with recurrence-free intervals of ≥12 months. Value is being examined in an ongoing phase 3 trial (GOG-213).
■Patients with a progression-free interval of ≥6 months have platinum-sensitive disease. Second-line platinum-based therapy, single agent or combination, improves survival in women with platinum-sensitive disease (Table 17.3).
■Recurrence within 6 months of initial platinum-based chemotherapy is defined as platinum-resistant disease. Progression while on initial chemotherapy is platinum-refractory disease.
■Sequential single-agent chemotherapy is preferred for platinum-resistant/refractory patients, due to increased toxicity without sufficient evidence of increased benefit of combinations (Table 17.3). Cisplatin/gemcitabine is the one regimen with RCT-documented benefit.
■There has been increasing interest in the use of molecularly targeted agents:
•Bevacizumab has modest activity in relapsed ovarian cancer, both platinum sensitive and platinum resistant, and ongoing studies are evaluating its use (OCEANS).
•PARP inhibitors have demonstrated clinical activity in recurrent EOC in BRCA1/2mut carriers in phase 1/2 studies.
Nonepithelial Ovarian Cancer
■Most patients with ovarian germ cell tumors are diagnosed with early-stage disease. Lymph node metastases are rare. Unilateral salpingo-oophorectomy, if contralateral ovary is uninvolved, is possible in women who wish to preserve fertility.
■BEP chemotherapy (bleomycin/etoposide/cisplatin) should be considered after surgery for germ cell tumors: nondysgerminoma, all but stage I grade 1 disease, and ≥ stage II dysgerminoma.
■Most ovarian sex-cord stromal tumors are low grade, early stage at presentation, and have excellent survival. Radiation to gross residual tumors and hormonal therapy with progestin for granulosa cell tumors are considered after surgical resection.
■Many malignant stromal tumors including granulosa cell tumors produce estrogen; hence, evaluation of the endometrium for malignant change is needed.
Radiation
Radiation therapy (RT) plays a limited role in the treatment of EOC in the United States. Tumors of ovarian and tubal origin are sensitive to RT. RT should be considered for solitary metastases with functional consequences (brain metastases, distal bowel obstruction, bleeding).
Experimental Therapy/Immunotherapy
Patients with ovarian cancer of all stages, at diagnosis and at recurrence, should be encouraged to participate in clinical trials (www.clinicaltrials.gov).
SUPPORTIVE CARE
Common Treatment Toxicities
■Myelosuppression: Carboplatin-related bone marrow suppression is a cumulative toxicity (see Chapter 34).
■Nausea/vomiting: Carboplatin is less emetogenic than cisplatin. Both acute and delayed nausea/vomiting should be monitored and addressed therapeutically (see Chapter 38).
■Renal dysfunction
•Great care should be taken in patients with borderline or abnormal renal function.
•Serum creatinine-based calculations of GFR underestimate renal dysfunction in patients who have received platinums.
■Neurotoxicity
•Both platinums and taxanes cause neuropathy. Platinums cause demyelinating injury and can leave long-lasting neuroresiduals. Taxanes and other chemotherapies cause axonal degeneration, which is recoverable.
•Grade 3 to 4 neuropathy can have long-term effects and may require substitution or discontinuation of the offending agent(s). Dose modification of drugs with grade 2 neuropathy may be needed to avoid grade 3 to 4 neuropathy.
■Perforation
•Bevacizumab causes a 5% to 11% risk of gastrointestinal perforation in EOC patients.
•Possible risk factors for perforation include previous irradiation, tumor involving bowel, and early tumor response.
■Obstruction
•Patients can present with both bowel and urinary tract obstruction. Presenting symptoms include nausea, vomiting, abdominal pain, abdominal distention, abdominal and/or back pain, and infrequent bowel movements or urination.
•Initial treatment for bowel obstruction may be conservative, with bowel rest and nasogastric suction, but many patients will require bypass surgery.
•The aggressiveness of intervention should be balanced with the patient’s prognosis, health status, and goals of care. Management with analgesics, antiemetics, anticholinergics, etc. and/or endoscopic placement of drainage tubes are options for poor surgical candidates.
•Urinary obstruction may be relieved with ureteral stents or nephrostomy, depending on the location, length, and severity of the obstruction.
•Occasionally, RT to a particular mass causing obstruction may be appropriate.
SUMMARY
■EOC is the most common cause of death among women with gynecologic malignancies and the fifth leading cause of cancer death in women in the United States.
■Limited disease with high-risk features and advanced disease need adjuvant paclitaxel/carboplatin.
■For women who experience a recurrence, the selection of therapy is commonly based upon response to initial platinum-based treatment.
ACKNOWLEDGMENT
This work was supported by the Intramural Program of the Center for Cancer Research, National Cancer Institute.
REVIEW QUESTIONS
1.The patient is a 54-year-old African-American woman who was diagnosed with stage IIIC high-grade serous ovarian 24 months ago. After an exploratory laparotomy resulted in successful resection of all gross disease, she received six cycles of intravenous paclitaxel/carboplatin with a resultant clinical complete remission. She now presents with a rising CA-125 (three successive monthly elevated values with the last value at 360). She is asymptomatic. A CT scan of the abdomen/pelvis shows no evidence of recurrent disease. Which of the following would you recommend at this point?
A.Observation
B.Exploratory laparotomy and secondary surgical cytoreduction
C.Insertion of an IP catheter and administration of IP cisplatin
D.Systemic chemotherapy with a carboplatin-based doublet
E.Systemic chemotherapy with an active agent to which she has not been previously exposed
2.A 40-year-old woman presents to her gynecologist because her sister, aged 42, was recently diagnosed with serous ovarian carcinoma and was found to carry a deleterious BRCA1 mutation. The patient reports a strong family history of both breast and ovarian cancer, also including her mother (breast cancer). Testing reveals that she also carries the deleterious BRCA1 mutation. She has completed her family, which of the following would you recommend?
A.Annual screening with transvaginal sonography and CA-125
B.Pelvic examination every 3 months
C.Annual screening with serum proteomic profiling
D.Risk-reducing salpingo-oophorectomy
E.Oral contraceptives
3.The patient is a 61-year-old Caucasian woman with increasing abdominal girth and discomfort beginning 3 months prior to seeing her gynecologist. The evaluation by the gynecologist revealed her to be in good health with no other significant problems. Physical examination observed a slightly distended abdomen and pelvic examination revealed a 6 cm mass in left adnexa. Laboratory data showed a CA-125 of 960. Computerized tomography of the abdomen showed a 7 cm mass involving the left ovary, ascites, and multiple scattered smaller masses throughout the abdomen. She underwent an exploratory laparotomy by a gynecologic oncologist with the identification of stage IIIC disease involving the peritoneal surface and omentum. At the conclusion of surgery, she had no gross disease remaining, and her CA-125 remained elevated, 34 units/mL, 4 weeks after surgery. Which of the following would be the best choice for treatment for this patient?
A.Paclitaxel/carboplatin for six cycles
B.IP chemotherapy with paclitaxel and carboplatin for six cycles
C.Docetaxel/carboplatin for six cycles
D.Gemcitabine/carboplatin for six cycles
E.Paclitaxel/carboplatin/bevacizumab for six cycles followed by maintenance bevacizumab until progression
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